U.S. patent number 5,043,325 [Application Number 06/829,285] was granted by the patent office on 1991-08-27 for n-6 substituted adenosine derivatives as cardiac vasodilators.
This patent grant is currently assigned to Whitby Research, Inc.. Invention is credited to Ray A. Olsson, Robert D. Thompson.
United States Patent |
5,043,325 |
Olsson , et al. |
August 27, 1991 |
N-6 substituted adenosine derivatives as cardiac vasodilators
Abstract
New, N-6 monosubstituted adenosine derivatives are disclosed
which have significant cardiac vasodilatory effect. The compounds
of the invention include 6-(cyclo-butyl
amino)-9-(.beta.-D-ribofuranosyl)-9H-purine, 6-(2-methyl-2-phenyl
hydrazino)-9-(.beta.-D-ribofuranosyl)-9H-purine, and compounds of
the general formula: ##STR1## wherein R.sub.1 is H, lower alkyl,
lower alkoxy, alkylamino, or arylamino, R.sub.2 is H, lower alkyl,
hydroxymethyl, phenyl or substituted phenyl, R.sub.3 is H, lower
alkyl, phenyl, substituted phenyl, R.sub.3 is H, lower alkyl,
phenyl, substituted phenyl, 2 or 3-thienyl, or 2 or 3-pyridyl,
R.sub.4 is H or lower alkyl, and R.sub.5 is H or lower acyl.
Particularly active as a cardiac vasodilator is the compound
(-)-6-(R-1-phenyl-2-butyl
amino)-9-(.beta.-D-ribofuranosyl)-9H-purine.
Inventors: |
Olsson; Ray A. (Odessa, FL),
Thompson; Robert D. (Tampa, FL) |
Assignee: |
Whitby Research, Inc. (Irvine,
CA)
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Family
ID: |
24407470 |
Appl.
No.: |
06/829,285 |
Filed: |
February 13, 1986 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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601435 |
Apr 18, 1984 |
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Current U.S.
Class: |
514/46; 514/45;
536/27.61; 536/27.7; 536/27.63 |
Current CPC
Class: |
C07H
19/16 (20130101); A61P 9/08 (20180101); A61P
9/10 (20180101) |
Current International
Class: |
C07H
19/00 (20060101); C07H 19/16 (20060101); A61K
031/70 () |
Field of
Search: |
;514/46 ;536/26 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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2007273 |
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Aug 1971 |
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DE |
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2139107 |
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Feb 1973 |
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DE |
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2426682 |
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Dec 1975 |
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DE |
|
Other References
Prasad, et al, "Modification of the 5'Position of Purine
Nucleosides, 2, Synthesis and Some Cardiovascular Properties of
Adenosine-5'-(N-substituted)carboxazmides", J. Med. Chem. 1980, 23,
313-319. .
Stein et al, "Cardiovascular Effects of Nucleoside Analogs", Annals
New York Acad. Sciences (1975) 225, 380-389. .
Stein, "Ethyl Adenosine-5'carboxylate, A Potent Vasoactive Agent in
the Dog", J. Med. Chem. (1973) 16:11, 1306-1208. .
Schwabe, "General Aspects of Binding of Ligands to Adenosine
Receptors", Chap. 6 Regulatory Function of Adenoisie, Berne et al,
77-96 (1983). .
Ukena, et al, .sup.6 -substituted 9-methyladenines: A New Class of
Adenosine Receptor Antagonists", FEBS Lett., 215 (2) 203-208
(1987). .
Robins et al, "Potential Purine Antagonists IV. Synthesis of Some
9-Methyl-6-substituted-purines", J. Am. Chem. Soc., 79, 490-494
(1957). .
Montgomery, et al, "Synthesis of Potential Anticancer Agents,
IX,9-Ethyl-6-substituted-purines", J. am. Chem. Soc., 79, 5238-5242
(1957). .
Myers, et al, "Alkylation of the Purine Nucleus by Means of
Quaternary Ammonium Compounds, I. Tetraalkylammonium Hydroxides",
J. Org. Chem., 28, 2089-2089 (1963). .
Fox, et al, "Binding Characteristics of an Adenosine, Receptor in
Human Placenta", J. Biol. Chem., 258(11), 6952-6955
(1983)..
|
Primary Examiner: Brown; Johnnie R.
Assistant Examiner: Crane; L. Eric
Attorney, Agent or Firm: Hackler; Walter A. Baran; Robert
J.
Parent Case Text
CROSS-REFERENCE TO RELATED APPLICATIONS
This is a continuation of application Ser. No. 601,435 filed Apr.
18, 1984, now abandoned.
Claims
What is claimed is:
1. A method of administering a compound of the formula ##STR8##
wherein R.sub.1 is H, a C.sub.1 to C.sub.4 lower alkyl group or an
alkoxy group having 1-4 carbon atoms;
R.sub.2 is H, C.sub.1 -C.sub.4 lower alkyl group, hydroxymethyl
group, phenyl group, C.sub.1 -C.sub.4 lower alkyl substituted
phenyl group, C.sub.1 -C.sub.4 lower alkoxy substituted phenyl
group;
R.sub.3 is H, C.sub.1 -C.sub.4 lower alkyl group, phenyl group,
C.sub.1 -C.sub.4 lower alkyl substituted phenyl group, mono-halogen
substituted phenyl group, C.sub.1 -C.sub.4 mono-lower alkoxy
substituted phenyl group, 2 or 3-thienyl group, C.sub.1 -C.sub.4
lower alkyl substituted 2 or 3-thienyl group, C.sub.1 -C.sub.4
lower alkoxy substituted 2 or 3-thienyl group, mono-halogen
substituted 2 or 3-thienyl group, 2 or 3-pyridyl group, C.sub.1
-C.sub.4 lower alkyl substituted 2 or 3-pyridyl group, C.sub.1
-C.sub.4 lower alkoxy substituted 2 or 3-pyridyl, pyridazinyl,
piperazinyl, pyrollyl or quinolinyl group, or mono-halogen
substituted 2 or 3-pyridyl group;
R.sub.4 is H, or a C.sub.1 -C.sub.4 lower alkyl group;
R.sub.5 is H, or an acyl group having 1-4 carbons;
X is C or N;
n is either 0 (zero) or 2;
m is either 0 (zero) or 1;
p is either 0 (zero) or 1;
with the provisos that when X is N then n is 0, m is 0 and p is 1,
when X is C and n is 0 then m is 1 and p is 1, when X is C and n is
2, then m is 0 and p is 0 and when X is C, n is 0, R.sub.2 is
methyl, R.sub.1 and R.sub.4 are H, then R.sub.3 is not phenyl;
to a mammal in need thereof, including humans and domestic animals,
in an effective dosage of said compound to obtain a cardiovascular
vasodilatory effect.
2. The method of claim 1 wherein R.sub.1 is H, R.sub.2 is H,
R.sub.4 is H, X is C, n is 0 (zero), and R.sub.3 is selected from a
group consisting of 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl,
mono-halogen substituted phenyl and C.sub.1 -C.sub.4 mono-alkoxy
substituted phenyl groups.
3. The method of claim 2 wherein R.sub.5 is H.
4. The method of claim 3 wherein R.sub.3 is 2-thienyl.
5. The method of claim 3 wherein R.sub.3 is 3-thienyl.
6. The method of claim 3 wherein R.sub.3 is 3-pyridyl.
7. The method of claim 3 wherein R.sub.3 is 2-pyridyl.
8. The method of claim 3 wherein R.sub.3 is 3-chlorophenyl.
9. The method of claim 3 wherein R.sub.3 is 2-methoxyphenyl.
10. The method of claim 3 wherein R.sub.3 is 4-fluorophenyl.
11. The method of claim 1 wherein R.sub.1 is H, R.sub.2 is H,
R.sub.3 is H, R.sub.4 is H, X is C and n is 2.
12. The method of claim 11 wherein R.sub.5 is H.
13. The method of claim 1 wherein R.sub.1 is H, R.sub.2 is phenyl,
R.sub.3 is H, R.sub.4 is H and X is N.
14. The method of claim 13 wherein R.sub.5 is H.
15. The method of claim 1 wherein R.sub.1 is H, R.sub.2 is methyl,
ethyl, propyl or hydroxymethyl, R.sub.3 is methyl, ethyl, phenyl,
C.sub.1 -C.sub.4 lower alkoxy substituted phenyl or mono-halogen
substituted phenyl, R.sub.4 is H, X is C and n is 0 (zero).
16. The method of claim 15 wherein R.sub.2 is ethyl, R.sub.3 is
methyl and R.sub.5 is H.
17. The method of claim 15 wherein R.sub.2 is propyl, R.sub.3 is
ethyl and R.sub.5 is H.
18. The method of claim 1 wherein R.sub.1 is H, R.sub.2 is H,
R.sub.3 is methyl or ethyl, R.sub.4 is phenyl, C.sub.1 -C.sub.4
lower alkyl substituted phenyl, C.sub.1 -C.sub.4 lower alkoxy
substituted phenyl, mono-halogen substituted phenyl, X is C and n
is 0 (zero).
19. The method of claim 18 wherein R.sub.4 is phenyl.
20. The method of claim 19 wherein R.sub.3 is methyl and R.sub.5 is
H.
21. The method of claim 19 wherein R.sub.3 is ethyl and R.sub.5 is
H.
22. A method according to claim 1 wherein said compound is (-)
-6-(S-2-butylamino)-9-(.beta.-D-ribofuranosyl)-9H-purine.
23. A method according to claim 1 wherein said compound is
(-)-6-(R-1-phenyl-2-butylamino)-9-(.beta.-D-ribofuranosyl)-9H-purine.
24. A method according to claim 1 wherein said compound is
(+)-6-(S-1-hydroxy-3-phenyl-2-propylamino)-9-(.beta.-D-ribofuranosyl)-9H-p
urine.
25. A method according to claim 1 wherein said compound is
(-)-6-(R-2-phenyl-1-propylamino)-9-(.beta.-D-ribofuranosyl)-9H-purine.
26. A method according to claim 1 wherein said compound is
(+)-6-(S-2-phenyl-1-propylamino)-9-(.beta.-D-ribofuranosyl)-9H-purine.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention is directed to certain N-6 substituted
adenosine derivatives which have beneficial cardiovascular activity
in mammals, including humans and domestic animals.
2. Brief Description of the Prior Art
Cardiovascular activities of adenosine, and of certain of its
derivatives, have been known in the art. German Offenlegungschrift
Nos. 2133273, 2426682, 1795761, 1913818, 2007273, 2238923, 2060189,
2244328, 1814711, 2136624, South African Patent Application No.
677630 (filed Dec. 20, 1967) and British Patent Specification No.
1,123,245 describe adenosine derivatives which have cardiovascular,
coronary dilator or antilipolytic activities.
In an article titled "Coronary Vasoactivity of Adenosine in the
Conscious Dog" Olsson et al. describe a bioassay of compounds for
cardiovascular activity. In the assay, the compounds to be tested
are infused intracoronarily into conscious, healthy dogs. The
naturally occurring nucleoside adenosine has a demonstrable
coronary dilator effect under these conditions. The concentration
of the test compound infused into the dog's heart, which causes
half-maximal coronary vasodilation is designated ED.sub.50.
More specifically, under the conditions of this assay, ED.sub.50 is
determined in the following manner. Late diastolic coronary
conductance (LDCC of the experimental dog is monitored through
suitable instrumentation. Late diastolic coronary conductance is
measured at maximum coronary vasodilation (peak reactive
hyperemia), and is designated LDCC.sub.max. Late diastolic coronary
conductance is also measured at basal coronary vasodilation, and is
designated LDCC.sub.o.
The difference between instantaneously measured late diastolic
coronary (LDCC) and basal late diastolic coronary conductance
(LDCC.sub.o) is expressed as a fraction of the difference between
maximum late diastolic coronary conductance (LDCC.sub.max) and
basal late diastolic coronary conductance (LDCC.sub.o). Thus
.DELTA.LDCC is defined by Equation I. ##EQU1##
As the concentration of the tested compound is varied, and the
corresponding .DELTA.LDCC is obtained through measurements and the
above-summarized calculations, data of an ".DELTA.LDCC versus
concentration" function or plot are obtained.
ED.sub.50 is derived from these data by log-logit transformation of
the ".DELTA.LDCC versus concentration" plot; namely by solving the
linear regression of logit (.DELTA.LDCC) on log (concentration) for
.DELTA.LDCC=0.5.
ED.sub.50 of tested compounds was found to provide good comparison
with data of the same or another compound tested on a different
experimental dog, when the ED.sub.50 of the particular compound is
related to ED.sub.50 of adenosine in the same experimental dog. As
is set forth in Equation II, molar potency ration (MPR) is defined
as the ratio of ED.sub.50 of adenosine to ED.sub.50 of the test
compound. Molar potency ration (MPR) is a useful measure of
cardiovascular vasodilatory effect, and hence of the utility of the
tested compound. ##EQU2##
It follows from the foregoing, that the greater is the vasodilatory
effect of a tested compound, the larger is the corresponding molar
potency ratio (MPR).
An article by J. W. Daly titled "Adenosine Receptors: Targets for
Future Drugs", Journal of Medicinal Chemistry 25, 197 (1982)
provides a summary of various theories regarding the physiological
role of adenosine and of certain adenosine analogs, agonists and
antagonists.
As the above referenced patents and articles demonstrate, the prior
art has provided and tested a relatively large number of adenosine
derivatives for cardiovascular, and vasodilatory activity.
Nevertheless, such derivatives having optimal biological properties
have remained an elusive goal for the prior art. As is known,
optimal biological properties include significant activity, absence
of undesirable side effects, and sufficient duration of the desired
activity.
The present invention is a significant development in the search
for such optimal compounds. Compounds of the present invention have
a novel structure and possess significant cardiovascular activity
thereby providing an array of cardiovascular, vasodilator agents
from which compounds having optimal characteristics as drugs for a
particular type of application, may be selected.
SUMMARY OF THE INVENTION
The present invention relates to new, N-6 monosubstituted adenosine
derivatives which have significant cardiovascular vasodilatory
activity. Compounds of the invention have the General Formula I,
##STR2##
Wherein R.sub.1 is H, a lower alkyl group, an alkoxy group having
1-4 carbon atoms, an alkylamino group, an arylamino group, lower
alkyl substituted arylamino group, lower alkoxy substituted
arylamino group, or halogen substituted arylamino group; R.sub.2 is
H, lower alkyl group, hydroxymethyl group, phenyl group, lower
alkyl substituted phenyl group, lower alkoxy substituted phenyl
group; R.sub.3 is H, lower alkyl group, phenyl group, lower alkyl
substituted phenyl group, monohalogen substituted phenyl group,
mono-lower alkoxy substituted phenyl group, 2 or 3-thienyl group,
lower alkyl substituted 2 or 3 thienyl group, lower alkoxy
substituted 2 or 3-thienyl group, mono-halogen substituted 2 or
3-thienyl group, 2 or 3 pyridyl group lower alkyl substituted 2 or
3-pyridyl group, lower alkoxy substituted 2 or 3-pyridyl group, or
mono-halogen substituted 2 or 3-pyridyl group; R.sub.4 is H, or a
lower alkyl group; R.sub.5 is H, or an acyl group having 1-4
carbons; X is C or N; n is either 0 (zero) or 2; m is either 0
(zero) or 1; p is either 0 (zero) or 1; with the provisos that when
X is N then n is 0, m is 0 and p is 1; when X is C and n is 0, then
m is 1 and p is 1; when X is C and n is 2, the m is 0 and p is 0;
and when X is C, n is 0, R.sub.2 is methyl, R.sub.1 and R.sub.4 are
H, then R.sub.3 is not phenyl.
Preferred examples within the scope of the invention are compounds
of the General Formula I wherein the 2 position of the purine
nucleus is unsubstituted, (R.sub.1 is H). Further preferred
examples are the nucleosides of General Formula I wherein the
hydroxl groups of the ribofuranose moiety are unsubstituted,
(R.sub.5 is H).
The nucleosidic compounds of the present invention are prepared by
nucleophilic displacement of a suitable leaving group (Y), such as
chloro, bromo, iodo, methylmercapto, from the 6 position of the
purine ribofuranosides of General Formula 2. Nucleophiles for the
displacement are primary amines or hydrazino compounds of the
General Formula 3. ##STR3##
The symbols R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, X, m, n
and p have the same definitions in General Formulae 2 and 3 as in
General Formula 1, and Y is the leaving group. In addition, R.sub.5
can be various acyl or alkali stable blocking groups commonly used
in carbohydrate and nucleoside chemistry.
Nucleosidic compounds of the present invention wherein the
1-position of the purine nucleus is unsubstituted (R.sub.1 is H),
and wherein the first atom in the substituent of the N-6 amino
group is carbon (X is C), are also prepared, in accordance with the
present invention, by alkali induced rearrangement of N-1
substituted adenosines of the General Formula 4. ##STR4##
In General Formula 4, the symbols R.sub.2, R.sub.3, R.sub.4, m, p
and n are defined as in General Formula 1. R.sub.5 symbolizes the
same groups as in General Formula 1, and also such alkali stable
sugar hydroxyl protecting groups as benzyl, ketal or acetal groups,
particularly isopropylidene or benziledene groups, which may be
removed by hydrogenation or acidolysis.
The N-6 monosubstituted adenosine derivatives of the present
invention are useful as cardiovascular agents and particularly as
vasodilators. Specific compounds of the invention have molar
potency ratios (MPR) in the range of 0.81 for 6- (4
heptylamino)-9-(.beta.-D-ribofuranosyl) -9H purine and 7.5 for
(-)-6-(R-1-phenyl-2-butylamino) -9-(.beta.-D-ribofuranosyl) - 9H -
purine.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of the present invention have the General Formula 1.
Preferred examples of compounds of the invention are N-6
monosubstituted adenosine nucleosides, namely compounds wherein the
2-position of the purine nucleus is unsubstituted; R.sub.1 is H in
General Formula 1. Furthermore, preferred nucleosides of the
present invention have free hydroxyl groups on the ribofuranose
moiety, (R.sub.5 is H in General Formula 1), although nucleosides
of General Formula 1 having acyl groups containing 1-4 carbon atoms
are also within the scope of the present invention. As is known,
such "lower" acyl groups are relatively readily split-off from
nucleoside hydroxyl groups under physiological conditions.
Compounds of the present invention include, as a subgroup,
nucleosides of General Formula 5. ##STR5##
Wherein Q is selected from aromatic ring systems including
heterocycles such as phenyl, pyridyl, thienyl pyridazinyl,
piperazinyl, pyrrolyl and quinolinyl nuclei, R.sub.1 is H, lower
alkyl, halogen, or lower alkoxy, and R.sub.2 is H or an acyl group
containing 1-4 carbons. However, when Q is phenyl then R.sub.1 is
not H.
Specific examples of compounds of the present invention which are
shown by General Formula 5 are given below. The molar potency ratio
(MPR) of each specific example and its melting point (m.p.) are
also listed next to the specific example. The molar potency ratios
of the compounds were determined in a manner which is generally
known in the art, and is briefly described in the introductory
portion of the present application for patent. Thus, examples of
compounds of General Formula 5 are:
6-[2-(2-thienyl) ethyl amino]-9 -(.beta.-D-ribofuranosyl)-9H -
purine; m.p. 153.degree.-4.degree.; MPR 4.01.
6-[2-(3-thienyl) ethyl amino]-9 -(.beta.-D-ribofuranosyl)-9H -
purine; m.p. 152.degree.-3.degree.; MPR 2.48.
6-[2-(2-pyridyl) ethyl amino]-9 -(.beta.-D-ribofuranosyl)-9H -
purine; m.p 124.degree.-6.degree.; MPR 0.83.
6-[2-(3-pyridyl) ethyl amino]-9 -(.beta.-D-ribofuranosyl)-9H -
purine; m.p 165.degree.-6.degree.; MPR 3.16.
6-[2-(3-chlorophenyl) ethyl amino]-9 -(.beta.-D-ribofuranosyl)-9H -
purine; m.p 128.degree.-130.degree.; MPR 1.34.
6-[2-(2-methoxyphenyl) ethyl amino]-9 -(.beta.-D-ribofuranosyl)-9H
- purine; m.p 145.degree.-6.degree.; MPR 1.20.
6-[2-(3-methoxyphenyl) ethyl amino]-9 -(.beta.-D-ribofuranosyl)-9H
- purine; m.p 110.degree.-11.degree.; MPR 1.25.
6-[2-(4-fluorophenyl) ethyl amino]-9 -(.beta.-D-ribofuranosyl)-9H -
purine; m.p 190.degree.-1.degree.; MPR 1.6.
A specific example of the compounds of the present invention shown
by General Formula 1, wherein X is C and n is 2, is 6 - (cyclobutyl
amino]- 9 - (.beta.-D-ribofuranosyl) - (9H -purine; m.p.
121.degree.-3.degree.. In the assay conducted on anesthetized
healthy dogs, as described in the introductory section of the
present application, this compound was found to have an MPR of
1.57.
Another specific example of the compounds of the present invention,
shown by General Formula 1, is the hydrazino derivative 6 -
(2-methyl-2-phenyl hydrazino)-9 -(.beta.-D-ribofuranosyl)-9H -
purine (X is N, R.sub.2 is phenyl, R.sub.3 and R.sub.4 are H in
General Formula 1) m.p. 127.degree.-9.degree.; MPR 1.75.
Still another subgroup of the N-6 substituted adenosine derivatives
of the present invention is shown by General Formula 6, wherein
R.sub.1 is methyl ethyl, propyl or hydroxymethyl, R.sub.2 is
methyl, ethyl, phenyl, lower alkyl substituted phenyl, lower alkoxy
substituted phenyl, or monohalogen substituted phenyl, or other
substituted or unsubstituted aromatic heterocycle, the chiral
center in the two carbon chain may have either R or S
configuration, and wherein R.sub.3 is H, or acyl containing 1-4
carbons. However, when R.sub.1 is methyl then R.sub.2 is not
phenyl. ##STR6##
Specific examples of compounds of General Formula 6 are:
(-)-6-(S-2-butyl amino)-9-(.beta.-D-ribofuranosyl)-9H-purine; m.p.
95.degree.-8.degree.; MPR 2.6, and its R enantiomer, m.p.
104.degree.-105.degree.; MPR 0.88.
6-(3-pentyl amino)-9-(.beta.-D-ribofuranosyl)-9H-purine; m.p.
90.degree.-100.degree.; MPR 4.0.
6-(4-heptyl amino)-9-(.beta.-D-ribofuranosyl)-9H-purine; m.p.
112.degree.-113.degree.; MPR 0.81.
(-)-6-(R-1-phenyl-2-butyl
amino)-9-(.beta.-D-ribofuranosyl)-9H-purine; m.p.
135.degree.-6.degree.; MPR 7.5.
(+)-6-S-1-hydroxy-3-phenyl-2 propyl
amino)-9-(.beta.-D-ribofuranosyl)-9H-purine; m.p.
96.degree.-100.degree.; MPR 1.6.
The high activity of (-)-6-(R-1-phenyl-2 butyl
amino)-9-(.beta.-D-ribofuranosyl)-9H-purine is particularly
important in view of the fact that the S enantiomer of this
compound is substantially inactive.
Yet another subgroup of the compounds of the present invention is
shown by General Formula 7, wherein R.sub.1 is methyl or ethyl,
R.sub.2 is phenyl and R.sub.3 is H, or acyl containing 1-4 carbons.
##STR7##
Specific examples of the N-6 monosubstituted adenosine derivatives
shown by General Formula 7 are:
(-)-6-(R-2-phenyl-1propyl
amino)-9-(.beta.-D-ribofuranosyl)-9H-purine; m.p.
93.degree.-95.degree.; MPR 2.4; and the S enantiomer of this
compound, m.p. 128.degree.-9.degree.; MPR 3.0.
6-(2-phenyl-1-butyl amino)-9-(.beta.-D-ribofuranosyl)-9H-purine
m.p. 96.degree.-100.degree.; MPR 3.5.
The N-6 monosubstituted adenosine derivatives of the present
invention can be prepared, in accordance with the present invention
by the following processes.
Purine nucleosides of General Formula 2, wherein Y represents a
leaving group, are reacted with a primary amine or a hydrazino
compound of the General Formula 3. The symbols R.sub.1, R.sub.2,
R.sub.3, R.sub.4, R.sub.5, X, m, n, p represent groups as defined
above in connection with these two general formulae. Y is a
suitable leaving group subject to nucleophilic displacement, and
can be e.g. a chloro, bromo, iodo, mercapto, substituted
benylmercapto, methylmercapto, benzylmercapto, mesyloxy, tosyloxy
or trimethylsilyloxy group.
The hydroxyl groups of the ribofuranose moiety can remain
unprotected for the nucleophilic displacement reaction.
Alternatively, when desired, these hydroxyl groups can be protected
by groups customarily used in sugar or nucleoside chemistry, such
as acyl, benzyl or substituted benzyl groups. The 2' and 3'
hydroxyl groups of the ribofuranose moiety may also be protected,
when desired, by acid labile ketal or acetal groups, such as
benzylidene or isopropylidene groups. As is known, during the
nucleophilic displacement reaction acyl blocking groups of the
sugar hydroxyls may be fully or partially cleaved. These groups are
readily removed by alkali, for example by treatment with sodium
methoxide in methanol. Benzyl blocking groups can be removed, by
mild catalytic hydrogenation, and acetal and ketal blocking groups
can be removed by acid.
6-chloro-9-(.beta.-D-ribofuranosyl)-9H-purine, 6
-chloro-9(tri-O-.beta.-D-ribofuranosyl) - 9H purine, at
6-chloro-9-(tri-O-benzoyl-.beta.-D-ribofuranosyl)-9H - purine are
particularly suitable starting materials for the above-noted
nucleophilic displacement reactions. Such starting compounds are
described, for example, in Coll. Czech, Chem. Comm. 3-, page 1880
(1965), and in J. Org. Chem. 28, page 945 1963).
The nucleophilic displacement reactions between compounds of
General Formulae 2 and 3 are advantageously conducted at elevated
temperatures, in inert solvents, such as alcohols, ethers, pyridine
or dimethylformamide. Ethanol, isopropanol, butanol,
tetrahydrofurane, and dioxane are examples of suitable alcohol or
ether type solvents.
Advantageously, an organic or inorganic acid acceptor, such as
triethylamine, or calcium carbonate, or both are General Formula 3
may act as the acid acceptor.
The nucleophilic displacement reaction may also be conducted at
room temperature, although in such a case the reaction times are
prolonged relative to reactions at elevated temperature. In the
event the reagent amine of General Formula 2 is low boiling the
reaction may be conducted by heating the reactants in a sealed
tube.
Conditions particularly suitable for conducting the nucleophilic
displacement reaction when 6 chloro - 9 -(.beta.-D-ribofuranosyl) -
9H - purine is the starting material, include heating the reactants
for approximately twenty hours in refluxing ethanol, with the
exclusion of atmospheric moisture, and in the presence of
triethylamine and calcium carbonate. Alternatively, an even more
preferred procedure is to reflux the reactants for approximately
twenty hours in absolute ethanol in the presence of excess
triethylamine. Preferably the course of the nucleophilic
displacement reaction is monitored through thin layer
chromatography, and the reaction is continued until completed.
In the event the Y leaving group gives rise to a volatile
by-product, such as methylmercaptane or benzylmercaptane, then use
of an acid acceptor is not necessary.
It should be understood, that instead of the free amines or
hydrazino compounds shown in General Formula 3, their corresponding
salts, such as the hydrobromide or hydrochloride, may also be used
in the nucleophilic displacement reaction. Similarly, in the event
the starting purine ribofuranoside of General Formula 2 contains an
amino group, (for example when R.sub.1 is an alkylamino or
arylalkylamino group) then salts of these purine ribofuranosides
are also suitable for use in the nucleophilic displacement
reaction.
In addition to the above noted nucleophilic displacement reaction,
certain 2-unsubstituted adenosine derivatives of the present
invention, (compounds of General Formula 1 wherein R.sub.1 is H and
X is C) can also be obtained by hot alkali induced rearrangement of
N-1 substituted adenosines, shown in General Formula 4.
In General Formula 4, R.sub.2, R.sub.3, R.sub.4, R.sub.5, m, p, and
n define groups described above in connection with General Formula
1. R.sub.5 also defines additional acyl blocking groups, as well as
alkali stable benzyl, substituted benzyl, ketal and acetal blocking
groups customarily used in carbohydrate and nucleoside
chemistry.
The starting compounds of General Formula 4, are obtained, in a
known manner, by alkylation of free adenosine, or of adenosine
derivatives which are suitably protected in the ribofuranose
moiety, with benzyl, ketal or acetal groups. The alkylating agents
correspond in their alkyl moiety to the N-1 substituent of General
Formula 4. Such alkylating agents must contain a suitable leaving
group, such as a chloro, bromo, iodo, or an alkyl, aryl, alkylaryl
or arylalkyl sulfonyloxy group.
As it should be readily appreciated by those skilled in the art,
acyl blocking groups are usually removed from the ribofuranose
moiety during the treatment with alkali which brings about the
desired N-1 to N-6 rearrangement. Benzyl, ketal or acetal blocking
groups, on the other hand, are readily removed, after the desired
rearrangement by acidolysis or hydrogenation.
As still another, although less preferred process, compounds of the
present invention may be obtained by N-9 glycosylation of the
appropriately substituted purine derivatives. The glycosylation can
be conducted under known conditions, such as heating of the
appropriately substituted purines with tri-0-benzoyl -
D-ribofuranosyl chloride or bromide in nitromethane in the presence
of a mercury salt.
The compounds of the present invention are useful as cardiac
vasodilators, in mammals, domestic animals and humans. Although
various modes of administering the compounds may become apparent
oral and topical administration and intravenous infusion are
presently preferred. Activity of the compounds as coronary
vasodilators is reflected by their molar potency ratio number.
Several pharmacologically accepted salts of the compounds of the
present invention can also be used as vasodilators.
SPECIFIC EXAMPLE
6-[2-(2-thienyl)ethyl]amino-9-(.beta.-D-ribofuranosyl)-9H-purine
A mixture of 6 - chloro - 9 (.beta.-D-ribofuranosyl) - 9H - purine
(1.5 g, 5.2 mmoles), 2-(2- aminoethyl)thiophene (0.7 g, 5.5 mmoles)
(the hydrochloride of the amine can also be used), triethylamine
(2.2 ml, 15.6 mmoles) and 50 ml of absolute ethanol was refluxed
for 20 hours. The solvents were removed in vacuo. Ether was added
to the residue, which precipitated the amine hydrochloride. The
amine hydrochloride was removed by filtration and the solvents were
removed in vacuo to give a foam. The foam was recrystallized from
methanol to give 1.5 g (76% as colorless needles, mp
153.degree.-154.degree.; u.v:.LAMBDA.max (.epsilon.), 270 nm
(18,500) at pH 7; nmr (DMSO-d.sub.6): 3.15 (t, 2H, CH.sub.2 -2),
3.52-5.50 (m, 10H, CH.sub.2 -1 and ribose), 5.88 (d, 1H, anomeric,
J.sub.1, 2 = 5.8 Hz), 6.92 [m, 2H, thienyl (H-3 and H-4)],7.29 (br
t, 1H, NH), 8.22 (s, 1H, H-8), 8.32 (s, 1H, H-2).
Anal Calcd. for C.sub.16 H.sub.19 N.sub.5 O.sub.4 S.1/2H.sub.2 O
(386.43): C, 49.73; H, 5.22; N, 18.12; S, 8.30; Found: C, 50.00; H,
5.20; N, 18 12; S, 8.17.
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